Oncogenic hijacking of the stress response machinery in T cell acute lymphoblastic leukemia.

HiC-bench: comprehensive and reproducible Hi-C data analysis designed for parameter exploration and benchmarking. Lazaris, C., Kelly, S., Ntziachristos, P., Aifantis, I. NOTCH1 extracellular juxtamembrane expansion mutations in T-ALL. CUTLL1, a novel human T-cell lymphoma cell line with t(7 9) rearrangement, aberrant NOTCH1 activation and high sensitivity to γ-secretase inhibitors. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia.

The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Acute lymphoblastic leukemia in children. NOTCH1–RBPJ complexes drive target gene expression through dynamic interactions with superenhancers. The genetics and mechanisms of T cell acute lymphoblastic leukaemia. Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Oncogenic Notch promotes long-range regulatory interactions within hyperconnected 3D cliques. Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking. CTCF establishes discrete functional chromatin domains at the Hox clusters during differentiation. CRISPR inversion of CTCF sites alters genome topology and enhancer/promoter function. Cohesin loss eliminates all loop domains.

Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization. Insulated neighborhoods: structural and functional units of mammalian gene control. CTCF: an architectural protein bridging genome topology and function. Stratification of TAD boundaries reveals preferential insulation of super-enhancers by strong boundaries. Master transcription factors and Mediator establish super-enhancers at key cell identity genes. Super-enhancers in the control of cell identity and disease. Spatial partitioning of the regulatory landscape of the X-inactivation centre. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. The 3D genome as moderator of chromosomal communication. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Disruptions of topological chromatin domains cause pathogenic rewiring of gene–enhancer interactions. Overall, our study highlights the impact, complexity and dynamic nature of 3D chromatin architecture in human acute leukemia. Moreover, our data also demonstrate that small-molecule inhibitors targeting either oncogenic signal transduction or epigenetic regulation can alter specific 3D interactions found in leukemia. Our studies identify and focus on a TAD ‘fusion’ event associated with absence of CTCF-mediated insulation, enabling direct interactions between the MYC promoter and a distal super-enhancer. Systematic integration of matched in situ Hi-C, RNA-seq and CTCF ChIP–seq datasets revealed widespread differences in intra-TAD chromatin interactions and TAD boundary insulation in T-ALL. Here we investigate the 3D chromatin architecture in T cell acute lymphoblastic leukemia (T-ALL) by using primary human leukemia specimens and examine the dynamic responses of this architecture to pharmacological agents. Differences in three-dimensional (3D) chromatin architecture can influence the integrity of topologically associating domains (TADs) and rewire specific enhancer–promoter interactions, impacting gene expression and leading to human disease.

Gro seq